Chen-Ming Fan

Generating Mouse Models for Human Genetic Diseases

Mouse models provide a powerful tool to study human diseases and to allow molecular testing of the underlying mechanisms involved. The primary goal of Fan's research is to generate mouse models for better understanding of human development and genetic diseases. The scientists hope that the information obtained through basic research will be used to find cures or minimize the impact of the genetic aberration.

The group has generated the mouse models lacking Sim1 and Sim2 function. Sim1 and Sim2 are two mouse homologs of the Drosophila sim gene, which controls the development of the central nervous system midline cells in the fly. The group has cloned and characterized these mouse Sim genes,² and both Sim1 and Sim2 gene functions have been inactivated in the mouse via homologous recombination.

The analyses of Sim1 mutant mice have led to the conclusion that Sim1 controls the development of the anterior periventricular nucleus, the paraventricular nucleus, and the supraoptic nucleus of the hypothalamus. Consequently, in the Sim1 mutant, the neuroendocrine peptide hormones such as corticotropin-releasing hormone, thyrotropin-releasing hormone, somatostatin, vasopressin, and oxytocin are not produced by the hypothalamus. The severe depletion of these homeostasis hormonal peptides most likely causes the perinatal lethality of Sim1 mutant mice.³ The scientists have also found that there was a mutant mouse generated in the 1960s that displayed identical hypothalamic phenotype as Sim1. They showed that Sim1 and this mutated gene Arnt2 are coexpressed in the hypothalamus and that their protein products can bind to each other, suggesting that they function together to control the development of the hypothalamus.⁴

To their surprise, Sim1 heterozygous mice are obese (Fig. 3). Recently, many of the genetic components involved in mouse obesity have been identified. While the lateral and ventral hypothalamic nuclei have been implicated to control satiety, the role of the paraventricular region in obesity is less clear. The researchers are currently investigating how Sim1 fits into the genetic pathway of obesity. An obese patient has been identified by Dr. Andrew Zinn of Southwestern University to carry a mutation in the SIM1 gene. Collaborative efforts have been initiated to use the Fan mouse model to understand this corresponding human condition and possibly develop a corrective procedure.

Preliminary analysis of the Sim2 mutant suggests that Sim2 is required for the proper development of specific craniofacial structures. The primary defects when this gene is absent are cleft palate, nasal bone abnormality, and trigeminal nerve reduction. This is consistent with the possibility that Sim2 may contribute to aspects of Down's syndrome pathology (the human SIM2 gene is located within the Down's syndrome "critical region" of chromosome 21). Detailed documentation of the affected cartilage and bones is the immediate goal. However, overexpression of Sim2 does not appear to recapitulate the trisomy phenotype of Down's syndrome (DS), most likely due to the requirement of multiple genes on chromosome 21 to reproduce the DS phenotype.

Fig. 3. An obese Sim1 heterozygous mouse is shown on the left. To the right is a control.

² Fan et al., MCN 7, 1-16, 1996.

³ Michaud et al., Genes & Development 12, 3264-3275, 1998.

⁴ Michaud et al., Mechanisms of Development, in press.